Asenapine belongs to the dibenzo-oxepino-pyrrole class of psychotropic agents and is a potent antagonist of dopamine and serotonin receptors. The maleate salt of Asenapine has been approved as a drug for the treatment of schizophrenia and psychosis in humans. During the clinical studies of Asenapine, it was observed that oral dosing of the drug in human patients was associated with serious cardiotoxic side effects including postural hypotension. However, further development demonstrated that these side effects can be minimized with sublingual or buccal delivery. This dosing regimen was extensively studied and a sublingual tablet form of Asenapine maleate is now available as Saphris® for human use.
As can be appreciated by those skilled in the art, the sublingual tablet formulation requires very specific physical properties of the drug substance and drug product since the drug must dissolve quickly in the small volume of saliva present in the mouth. It is reported that a sublingual tablet must disintegrate in less 30 seconds for good efficacy.
Two crystalline forms of Asenapine maleate are known. One form, commonly referred as form H, has monoclinic crystals and melts at 141-145° C. The crystals of other form, commonly called form L, are orthorhombic and melting point of 138-142° C. Form H crystals are easily produced by crystallization from ethanol and the particles of crystals are about 100 micron when viewed under a micrograph. These crystals do not have the desired dissolution profile for sublingual use. The L form crystals of are smaller and have the requisite physiochemical properties but must be produced under very specific crystallization procedure. In the past, micronization of form H to reduce the crystal size was also tried but during micronization form H (orthorhombic) is converted to form L (monoclinic) to varying degree. It has been very difficult to control this transformation. Since the two forms have such divergent physicochemical properties, a mixture with variable amounts of two forms cannot be used in the preparation of a uniform dosage form required for a commercial product. The currently marketed sublingual tablet of Saphris is made using form L in a complex lyophilization process.
Thus, there is a need for a simple sublingual dosage form of Asenapine amenable for commercial production.
US 2017/0007537, assigned to Hetero Research Foundation, discloses liquid spray compositions comprising Asenapine for administration through oral mucosa. These compositions rely on penetration enhancer, particularly diethylene glycol monoethyl ether. There is no indication if the formulations are stable for an extended period of time. A solution of Asenapine maleate in polyol such as propylene glycol develops a yellow color during storage and therefore is not suitable as a commercial dosage form.
WO 2010127674 discloses liquid pharmaceutical Asenapine formulations that can be aerosolized or sprayed. However, these formulations are for transdermal delivery.
There is still a need for liquid Asenapine formulations that can be delivered orally and that are simple to manufacture.
There is particularly a need for liquid Asenapine formulations that can be delivered orally and that have excellent stability.
There is further a need for liquid compositions of Asenapine that can be delivered orally in a multi dose device.
There is a need for oral liquid compositions of Asenapine that can be supplied for a month of dosing (60 doses).